Photoredox catalyzed C(sp3)[sbnd]C(sp) coupling of dihydropyridines and alkynylbenziodoxolones

Article abstract of DOI:10.1016/j.tetlet.2019.151230

A visible light mediated deformylative alkynylation of aldehydes is presented. Under photo irradiation, 1,4-dihydropyridine (DHP), derived from an aldehyde, generated a C(sp³)- radical which couples with an alkynylbenziodoxolone to generate an

Full text of DOI:10.1016/j.tetlet.2019.151230

Journal Pre-proofs
Photoredox catalyzed C(sp3)-C(sp) coupling of dihydropyridines and alkynyl-
benziodoxolones
Shengzong Liang, Ricardo A. Angnes, Chinmay S. Potnis, Gerald B. Hammond
PII:
S0040-4039(19)31010-X
https://doi.org/10.1016/j.tetlet.2019.151230
TETL 151230
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
9 August 2019
27 September 2019
30 September 2019
Please cite this article as: Liang, S., Angnes, R.A., Potnis, C.S., Hammond, G.B., Photoredox catalyzed C(sp3)-C(sp)
coupling of dihydropyridines and alkynylbenziodoxolones, Tetrahedron Letters (2019), doi: https://doi.org/
10.1016/j.tetlet.2019.151230
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A visible light mediated deformylative alkynylation of aldehydes is
presented. Under photo irradiation, 1,4-dihydropyridine (DHP), derived
from an aldehyde, generated a C(sp3)- radical which couples with
alkynylbenziodoxolone, to generate an alkyl coupling product. This
strategy is mild and easy to operate, and a wide range of functional
groups are tolerated
Photoredox catalyzed C(sp3)-C(sp) coupling of dihydropyridines and alkynylbenziodoxolones
†
†
Shengzong Liang,b Ricardo A. Angnes,a Chinmay S. Potnis,b Gerald B. Hammond b,*

1
Tetrahedron Letters
Photoredox catalyzed C(sp3)-C(sp) coupling of dihydropyridines and
alkynylbenziodoxolones
†
†
Shengzong Liang,b Ricardo A. Angnes,a Chinmay S. Potnis,b Gerald B. Hammond b,*
a. Chemistry Institute, State University of Campinas - Unicamp C.P. 6154, CEP.13083-970, Campinas, São Paulo, Brazil
b. Department of Chemistry, University of Louisville, Louisville, Kentucky, 40292, United States.
† These authors contributed equally
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A visible light mediated deformylative alkynylation of aldehydes is presented. Under photo
irradiation, 1,4-dihydropyridine (DHP), derived from an aldehyde, generated a C(sp3)- radical
which couples with an alkynylbenziodoxolone to generate an alkyl substituted alkyne coupling
product. This strategy is mild and easy to operate, a wide range of functional groups were
tolerated, and 16 examples of products with 35-86% yields were obtained.
Available online
Keywords:
Photoredox
Alkynylbenziodoxolones.
Deformylative C-C bond formation
Alkynylation
2009 Elsevier Ltd. All rights reserved.
Introduction
Carbon-carbon bond formation has long remained at the center stage
of organic chemistry method development.1-3 Despite the advances
accumulated via transition metal catalysis, certain cross couplings
reactions are still challenging.4 The use of nickel/photoredox and
other dual catalysis have allowed a number of such methodologies to
be developed.5-9 However, circumventing the need for an extra
catalyst makes these methodologies more synthetically appealing.
Strategies that do not require dual catalysis were employed for the
alkynylation of alkyl radicals generated from potassium
trifluoroborates,10
N-phthalimidoyl
oxalates,11
N-
acyloxyphthalimides,10 iodides,12, 13 carboxylate ions,14-17 pyridinium
ions,18 C-C bonds,19-23 C-H bonds,24-28 and alkene capture of other
radicals.29, 30 However these reactions generally require the use of
additional oxidants, bases, radical initiators, or co-solvents. We
reasoned that the use of alkynylbenziodoxolones and
dihydropyridines (DHPs) as a mild radical source,31-48 would allow
for simpler, more amenable, reaction conditions.
Scheme 1: Photoredox alkynylation of alkyl radicals.
Herein we report on an alternative photoredox catalyzed C(sp3)-
C(sp) coupling of DHPs and alkynylbenziodoxolones. The reaction
is redox neutral and can be carried out at room temperature in plain
acetonitrile; also, it does not require any additional radical initiator,
which renders this protocol more practical and straightforward.
We started our investigation with the C(sp3)-C(sp) bond
While the present work was being carried out, a similar
strategy for the coupling of DHPs and alkynylbenziodoxolones was
reported (Scheme 1).23 This strategy requires moderate heating and a
binary solvent mixture (MeCN/H2O). Moreover, stoichiometric
amounts of K2S2O8 were employed as radical initiator (Scheme 1).23
formation of 5a and Ph-EBX (Table 2). To our delight, the use of 1

2
Tetrahedron
mol% Ir(ppy)3 in acetonitrile led to 95% yield of the desired
Substrate compatibility was also evaluated for the DHPs. Free
alcohols and Boc protected amines were well tolerated (61 and 85%
yield for 1ca and 1ba respectively; Table 3). Substrates containing
thiophene, indole, thiazole, succinimide and benzofuranone moieties
delivered the corresponding C(sp3)-C(sp) bond formation products in
moderate yields (35-47% yield; 1ia, 1fa, 1ha, 1ga and 1ja). On the
other hand, compounds containing simpler alkyl or aryl substituents
led to higher yields (73-86% yield; 1da, 1ea and 1aa; Table 3).
product 1aa (entry 1). Addition of Cs2CO3 to this reaction had a
detrimental effect, lowering the yield to 51% (entry 2). Catalyst
screening revealed that the reaction could be carried out in moderate
to high yields with most common photoredox catalysts (51-75%) but
optimal yields are achieved with Ir(ppy)3 (entry 1 and entries 3-7).
Similarly, solvent screening did not lead to any improvement (entries
8 and 9). Removal of either photocatalyst or light led to low yields
(3% and 5% yields respectively; entries 10 and 11). Moreover, in
accordance with a radical mechanism, the reaction showed itself
sensible to the presence of oxygen, thus when it was carried out
under air atmosphere the yield dropped to 15% (entry 12).
Table 3. Scope of dihydropyridines.
Table 1. Reaction optimization for C(sp3)-C(sp) coupling.
Entry
Photo-Catalyst
(1 mol %)
Ir(ppy)3
Modification
Solvent Result
(%)
1
2
-
MeCN
MeCN
95
51
Ir(ppy)3
Cs2CO3
(1.5 eq)[a]
3
4
5
6
7
8
9
10
11
12
Ru(bpy)3Cl2
Catalyst 1[b]
4CzIPN
Catalyst 2[c]
Eosin Y
Ir(ppy)3
Ir(ppy)3
-
-
-
-
-
-
-
-
-
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
57
51
75
72
63
0
78
3
5
Reaction conditions: DHP 5 (0.1 mmol), ethynylbenziodoxole PhEBX (0.15
mmol) and Ir(ppy)3 (1 mol %) MeCN (500μL), rt, 24 h.
A plausible reaction mechanism for this transformation is provided
in Scheme 2. The reaction inhibition by O2 is indicative of a radical
mechanism while the poor results obtained in absence of light
suggest the involvement of a photoredox catalytic cycle. As
described by Melchiorre and coworkers, dihydropyridines 5 can
cleave homolytically under photoirradiation with violet light
generating the corresponding alkyl radicals.[49] We believe such a
process could be sufficiently present in our system to initiate the
catalytic cycle by allowing the formation of catalytic amounts of the
DCM
MeCN
MeCN
MeCN
Ir(ppy)3
Ir(ppy)3
no LED[d]
presence of O2
[e]
15
[a] 1.5 equivalents of Cs2CO3 added as a base to the reaction conditions[b] 9-
Mesityl-10-methylacridinium. [c] Ir[dF(CF3)ppy]2(dtbpy)3. [d]no LED or any
source of light. [e] under air atmosphere.
iodoradical
6
(after trapping of the alkyl radical by
ethynylbenziodoxoles).[23] After this initiation, the catalytic cycle
would could kept going via oxidative quenching of the photocatalyst
exited state by the iodoradical 6, generating compound 7 and the
oxidized form of the photocatalyst. The latter could oxidize the
DHPs 5 generating compound 9 and alkyl radical that would restart
the cycle.
The alkynylation of DHP 5a could be performed with both electron
rich and electron poor ethynylbenziodoxazolones. Substrates
containing fluoride, chloride, trifluoromethoxy ethers, nitriles and
ketones underwent C(sp3)-C(sp) bond formation in yields ranging
from 66 to 82% (Table 2).
Table 2. Scope of ethynylbenziodoxoles.
Scheme 2: Plausible reaction mechanism.
Reaction conditions: DHP 1 (0.1 mmol), ethynylbenziodoxole 3 (0.15 mmol)
and Ir(ppy)3 (1 mol %) MeCN (500μL), rt, 24 h.

3
Conclusion
In summary we report on a room temperature, photoredox catalyzed,
reaction that we anticipate will, thanks to its simplicity, find use on
C(sp3)-C(sp) bond forming. The procedure does not require any
additional catalyst, radical initiator or co-solvent. Since the DHPs
can be readily prepared from the corresponding aldehydes, the
procedure achieves formal deformylative C-C bond formation. The
functional group tolerance was illustrated with substrates with
diverse reactivity.
Experimental
General procedure for synthesis of alkyne coupling product 1: DHP
5 (0.1 mmol), ethynylbenziodoxole 3 (0.15 mmol) and Ir(ppy)3 (0.8
mg, 1 mol %) were added to an oven-dried vial equipped with a
PTFE-coated magnetic stir bar. Then the vial was capped and purged
with three cycles of vacuum/argon. Subsequently, degassed solvent
MeCN (500 μL) was added through syringe under argon atmosphere.
The reaction mixture was vigorously stirred for 24 h at rt under
irradiation of blue LEDs. Then the vial was removed from the light
source and the solid was filtered off. The filtrate was concentrated
under reduced pressure and the crude product residue was purified
by either flash column chromatography on silica gel or preparative
TLC to give 1.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We are grateful to the U.S. National Science Foundation (grant
CHE-1401700 and 1855972) for support. R.A.A. is thankful for
grant 2017/01779-2, São Paulo Research Foundation
(FAPESP).

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5



Certain cross couplings reactions may be
challenging or require chemical adjuvants.
Photoredox C(sp3)-C(sp) coupling of DHPs
and alkynylbenziodoxolones is feasible.
The
deformylative C-C bond formation.
Functional group tolerance is noteworthy.
procedure
achieves
formal
